EP0188194A2 - Aminoacrylic acid derivatives - Google Patents

Aminoacrylic acid derivatives Download PDF

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Publication number
EP0188194A2
EP0188194A2 EP86100052A EP86100052A EP0188194A2 EP 0188194 A2 EP0188194 A2 EP 0188194A2 EP 86100052 A EP86100052 A EP 86100052A EP 86100052 A EP86100052 A EP 86100052A EP 0188194 A2 EP0188194 A2 EP 0188194A2
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Prior art keywords
formula
chloro
fluoro
alkyl
acid derivatives
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EP86100052A
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German (de)
French (fr)
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EP0188194B1 (en
EP0188194A3 (en
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Fritz Dr. Maurer
Klaus Dr. Grohe
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/825—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups all hydroxy groups bound to the ring

Definitions

  • the present invention relates to new aminoacrylic acid derivatives, a process for their preparation and their use as an intermediate for the preparation of oxoquinoline carboxylic acid derivatives.
  • oxoquinoline carboxylic acid derivatives can be prepared in a simpler manner and therefore more cost-effectively than from the prior art is known (cf. EP-OS 78 362).
  • the substituted ethyl benzoylacetates are prepared by saponifying, for example, trihalomethylbenzene derivatives, converting the acid with thionyl chloride to the corresponding benzoyl chloride and then reacting it with diethyl malonate in the presence of magnesium alcoholate to give the benzoylmalonic ester derivative.
  • the benzoylacetic acid ethyl ester is formed by partial saponification and decarboxylation in an aqueous medium with catalytic amounts of p-toluenesulfonic acid.
  • the further reaction of the ethyl benzoylacetate is initially carried out analogously to the process specified in EP-OS 78 362 by reaction with O-formic acid ester and subsequent reaction with amines. This is followed by ring closure in the presence of acid acceptors and with the elimination of alcohol.
  • These compounds can then react further by known methods to give the corresponding oxoquinoline carboxylic acid derivatives (cf., for example, EP-OS 78 362).
  • Formula (II) provides a general definition of the acrylic acid derivatives to be used as starting materials for process (2) according to the invention.
  • R and R preferably represent those radicals which are given above for formula (I).
  • R 3 in this formula represents alkoxy.
  • R 3 is preferably C 1 -C 4 alkoxy.
  • the compounds of formula (II) are new. They can be manufactured according to 4 (above) (see below).
  • Formula (III) provides a general definition of the amines also to be used as starting materials for process (2) according to the invention.
  • R 2 preferably represents those radicals which are given above for formula (I).
  • the compounds of formula (III) are generally known compounds of organic chemistry.
  • Process (2) according to the invention for the preparation of the new compounds of the formula (I) is preferably carried out using diluents. Practically all inert organic solvents can be used as diluents.
  • aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene, o-dichlorobenzene, ethers such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane and alcohols such as methanol, ethanol, isopropanol, glycol.
  • hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform
  • Process (2) according to the invention is generally carried out at temperatures between -20 ° C. and + 50 ° C. The range between -10 ° C and 30 ° C is preferred. The reactions are generally carried out under normal pressure.
  • the starting materials are usually used in approximately equimolar amounts.
  • An excess of one or the other reaction component has no significant advantages.
  • the processing takes place according to usual methods.
  • reaction can be represented by the following formula:
  • Formula (IV) provides a general definition of the 2-alkoxy-4-chloro-5-fluorobenzoylacetic acid esters to be used as starting materials for process (4) according to the invention.
  • R preferably represents those radicals which are given above for formula (I).
  • R 4 in this formula represents alkyl.
  • R 4 is preferably C 1 -C 4 alkyl, particularly preferably methyl, ethyl, isopropyl or butyl.
  • the compounds of formula (IV) are new. They can be manufactured according to 6 (above) (see below).
  • Formula (V) provides a general definition of the orthoformic acid esters to be used as starting materials for process (4) according to the invention.
  • R 3 in this formula represents alkoxy.
  • R 3 is preferably C'-C4-alkoxy.
  • the compounds of formula (V) are generally known compounds of organic chemistry.
  • Process (4) according to the invention for the preparation of the compounds of the formula (II) is preferably carried out without a diluent.
  • Process (4) according to the invention is generally carried out at temperatures between 80 ° C. and 180 ° C. The range between 100 ° C. and 160 ° C. is preferred. The reactions are generally carried out under normal pressure.
  • reaction can be represented by the following formula:
  • Formula (VI) provides a general definition of the acetophenones to be used as starting materials for process (6) according to the invention.
  • R preferably represents those radicals which are given above for formula (I).
  • the compounds of formula (VI) are new. They can be manufactured according to 8 (above) (see below).
  • Formula (VII) provides a general definition of the dialkyl carbonates to be used as starting materials for process (6) according to the invention.
  • R 4 represents alkyl.
  • R4 is preferably C 1 -C 4 alkyl.
  • the compounds of formula (VII) are known compounds of organic chemistry.
  • Process (6) according to the invention for the preparation of the compounds of the formula (IV) is preferably carried out without a diluent. It is preferred to work in the presence of excess dialkyl carbonate of the formula (VII).
  • Process (6) according to the invention is carried out in the presence of strong bases.
  • Alkaline alcoholates such as sodium and potassium methylate or ethylate
  • potassium tert-butoxide and alkali metal hydroxides such as sodium and potassium hydroxide
  • Process (6) according to the invention is generally carried out at temperatures between 0 ° C. and 140 ° C. The range between 20 ° C and 120 ° C is preferred. The reactions are generally carried out under normal pressure.
  • Process (6) according to the invention is based on 1 mol of the compound of the formula (VI), 1 to 3 mol, preferably 1 to 2.0 mol of a strong base and 5 to 30 mol, preferably 10 to 25 mol of dialkyl carbonate of the formula (VII ) a.
  • the processing takes place according to usual methods.
  • reaction can be represented by the following formula:
  • Formula (IX) and (X) generally define the alkyl halides or dialkyl sulfates to be used as starting materials for process (8) according to the invention.
  • R preferably represents those radicals which are given above for formula (I).
  • Process (8) according to the invention for the preparation of the compounds of (VI) is preferably carried out in the presence of water or polar organic solvents.
  • Ketones such as e.g. Acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, also nitriles such as e.g. Acetonitrile and propionitrile, also amides, such as dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone, and ethers, such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane.
  • strongly basic but weakly nucleophilic substances can preferably be used as acid acceptors will.
  • Sodium hydride, potassium hydride, calcium hydride, sodium carbonate, potassium carbonate and calcium carbonate and diazabicyclooctane (DABCO), diazabicyclonones (DBN) and diazabicycloundecene (DBU) are preferred.
  • reaction temperature in process (8) according to the invention for the preparation of the new compounds of the formula (II) can be varied within a substantial range. In general, temperatures between 0 ° C and + 100 ° C , preferably between 0 ° C and 80 ° C. Process (8) according to the invention is generally carried out under normal pressure.
  • the reactions are generally carried out in a suitable diluent and, if appropriate, in the presence of an acid acceptor.
  • the processing takes place according to usual methods.
  • reaction can be represented by the following formula:
  • the compound 3-chloro-4-fluorophenol of the formula (XI) is used as the starting compound.
  • 3-chloro-4-fluorophenol is a well known compound of organic chemistry.
  • Formula (XII) provides a general definition of the acetylating agents which are also to be used as starting materials for process (10).
  • W represents halogen, such as, in particular, fluorine, chlorine or bromine or the remainder CH 3 COO-.
  • the compounds of the formula (XII) are generally known compounds of organic chemistry.
  • the acylation is carried out in the presence of known acylation catalysts.
  • Friedel-Crafts catalysts are preferred acylation catalysts for process (10). These include aluminum halides such as aluminum trichloride and boron trifluoride.
  • Process (10) according to the invention is preferably carried out without a diluent.
  • Process (10) according to the invention is generally carried out at temperatures between 0 ° C. and 120 ° C. The range between 20 ° C and 100 ° C is preferred. The reactions are generally carried out under normal pressure.
  • the processing takes place in the usual way e.g. by adding ice or ice water to the Rekaiton mixture after the reaction has ended and by suctioning off the cooled product.
  • the cyclization of the compounds of formula (I) to the known compounds of formula (XIII) is carried out in the presence of diluents and in the presence of acid acceptors at temperatures between 60 ° C to 300 ° C, preferably at 80 ° C to 180 ° C.
  • Dioxane, dimethyl sulfoxide, N-methyl-pyrrolidone, sulfolane, hexamethylphosphoric acid triamide and preferably N, N-dimethylformamide can be used as diluents.
  • Potassium tert-butoxide, butyl lithium, lithium phenyl, phenyl magnesium bromide, sodium methylate, sodium hydride and particularly preferably potassium or sodium carbonate are suitable acid acceptors for this reaction.
  • reaction product is worked up in a conventional manner.
  • the further reactions of the compounds of the formula (XIII) to the known compounds of the formulas (XIV) and (XV) have already been described (see e.g. EP-OS 78 362 and EP-OS 113 092).

Abstract

Aminoacrylic and derivatives of the formula <IMAGE> in which R is alkyl, R1 is alkoxycarbonyl, and R2 is alkyl, cycloalkyl, amino, alkylamino or dialkylamino, and intermediates therefor. The compounds can be converted into antibacterially active known oxyquinolinecarboxylic acid derivatives.

Description

Die vorliegende Erfindung betrifft neue Aminoacrylsäure-Derivate, ein Verfahren zu ihrer Herstellung, sowie ihre Verwendung als Zwischenprodukt zur Herstellung von Oxochinolincarbonsäure-Derivaten.The present invention relates to new aminoacrylic acid derivatives, a process for their preparation and their use as an intermediate for the preparation of oxoquinoline carboxylic acid derivatives.

Es ist bereits bekannt, daß man Oxochinolincarbonsäure-Derivate erhalten.kann, wenn man Aminoacrylsäure-Derivate als Zwischenprodukte einsetzt. Die Herstellung dieser Aminoacrylsäure-Derivate ist jedoch aufwendig und erfolgt in mehreren Stufen (vgl. z.B. EP-OS 78 362).It is already known that oxoquinoline carboxylic acid derivatives can be obtained if aminoacrylic acid derivatives are used as intermediates. However, the preparation of these aminoacrylic acid derivatives is complex and takes place in several stages (see e.g. EP-OS 78 362).

Die vorliegende Erfindung betrifft:

  • 1. Neue Aminoacrylsäure-Derivate der Formel (I)
    Figure imgb0001
    in welcher
    • R für Alkyl steht,
    • R für Alkoxycarbonyl steht und
    • R 2 für Alkyl, Cycloalkyl, Amino, Alkylamino oder Di-alkylamino steht.
  • 2. Ein Verfahren zur Herstellung der neuen Aminoacrylsäure-Derivate der Formel (I)
    Figure imgb0002
    in welcher
    • R für Alkyl steht,
    • R1 für Alkoxycarbonyl steht und
    • R 2 für Alkyl, Cycloalkyl, Amino, Alkylamino oder Di-alkylamino steht,

    das dadurch gekennzeichnet ist, daB man Acrylsäure-Derivate der Formel (II)
    Figure imgb0003
    in welcher
    • R und R1 die bei 1 (oben) angegebene Bedeutung haben und
    • R 3 für Alkoxy steht
    • mit Aminen der Formel (III)
      Figure imgb0004
      in welcher
    • R 2 die bei 1 (oben) angegebene Bedeutung hat,
    • gegebenenfalls in Gegenwart von inerten Verdünnungsmitteln umsetzt.
    • Acrylsäure-Derivate der Formel (II)
      Figure imgb0005
      in welcher
    • R, R1 und R3 die bei 2 (oben) angegebenen Bedeutungen haben.
  • 4. Ein Verfahren zur Herstellung der neuen Acrylsäure-Derivate der Formel (II),
    Figure imgb0006
    in welcher
    • R, R und R3 die bei 2 (oben) angegebenen Bedeutungen haben,
    • das dadurch gekennzeichnet ist, daß man 2-Alkoxy-4-chlor-5-fluor-benzoylessigsäureester der Formel (IV)
      Figure imgb0007
      in weicner
    • R die oben angegebene Bedeutung hat und
    • R4 für Alkyl steht, mit Orthoameisensäureestern der Formel (V)
      Figure imgb0008
      in welcher
    • R 3 die oben angegebene Bedeutung hat, in Gegenwart von Acetanhydrid und gegebennfalls in Gegenwart von Verdünnungsmitteln umsetzt.
  • 5. 2-Alkoxy-4-chlor-5-fluor-benzoylessigsäureester der Formel (IV)
    Figure imgb0009
    in welcher
    • R und R 4 die bei 4 (oben) angegebenen Bedeutungen haben.
  • 6. Ein Verfahren zur Herstellung der neuen 2-Alkoxy-4-chlor-5-fluor-benzoylessigsäureester der Formel (IV),
    Figure imgb0010
    in welcher
    • R und R4 die bei 4 (oben) angegebenen Bedeutungen haben,
    • das dadurch gekennzeichnet ist, daß man Acetophenone der Formel (VI)
      Figure imgb0011
      in welcher
    • R die bei 5 (oben) angegebene Bedeutung hat,
    • mit Kohlensäuredialkylestern der Formel (VII)
      Figure imgb0012
      in welcher
    • R 4 die bei 5 (oben) angegebene Bedeutung hat, in Gegenwart von starken Basen umsetzt
  • 7. Acetophenone der Formel (VI)
    Figure imgb0013
    in welcher
    • R die bei 5 (oben) angegebene Bedeutung hat.
  • 8. Ein Verfahren zur Herstellung der Acetophenone der Formel (VI),
    Figure imgb0014
    in welcher
    • R die bei 5 (oben) angegebene Bedeutung hat,
    • das dadurch gekennzeichnet ist, daß man 4-Chlor-5-fluor-2-hydroxacetophenon der Formel (VIII)
      Figure imgb0015
    • α) mit Allylhalogeniden der Formel (IX)
      Figure imgb0016
      in welcher
    • R die oben angegebene Bedeutung hat und
    • Hal für Halogen steht, oder
    • ß) mit Dialkylsulfaten der Formel (X)
      RO-SO2-OR (X) in welcher
    • R die oben angegebene Bedeutung hat, in Gegenwart von Säureakzeptoren und in Gegenwart von Verdünnungsmitteln umsetzt.
  • 9. 4-Chlor-5-fluor-2-hydroxyacetophenon der Formel (VIII)
    Figure imgb0017
  • 10. Verfahren zur Herstellung von 4-Chlor-5-fluor-2-hydroxyacetophenon der Formel (VIII), dadurch gekennzeichnet, daß man 3-Chlor-4-fluorphenol der Formel (XI)
    Figure imgb0018
    mit Acetylierungsmitteln der Formel (XII)
    Figure imgb0019
    in welcher
    • W für Halogen oder den Rest CH3-COO- steht,

    in Gegenwart von Acylierungskatalysatoren und gegebenenfalls in Gegenwart von Verdünnungsmitteln umsetzt.
  • 11. Verwendung von Verbindungen der Formel (I) gemäß 1 (oben), zur Herstellung von Oxochinolincarbonsäure-Derivaten, dadurch gekennzeichnet, daß man die Verbindungen der Formel (I) cyclisiert und anschließend nach bekannten Methoden zu Oxochinolincarbonsäure-Derivaten umsetzt (vgl. z.B. EP-OS 78 362 ).
The present invention relates to:
  • 1. New aminoacrylic acid derivatives of the formula (I)
    Figure imgb0001
     in which
    • R represents alkyl,
    • R represents alkoxycarbonyl and
    • R 2 represents alkyl, cycloalkyl, amino, alkylamino or di-alkylamino.
  • 2. A process for the preparation of the new aminoacrylic acid derivatives of the formula (I)
    Figure imgb0002
     in which
    • R represents alkyl,
    • R 1 represents alkoxycarbonyl and
    • R 2 is alkyl, cycloalkyl, A mino, alkylamino or di-alkylamino,

    which is characterized in that acrylic acid derivatives of the formula (II)
    Figure imgb0003
     in which
    • R and R 1 have the meaning given at 1 (above) and
    • R 3 is A lkoxy
    • with amines of the formula (III)
      Figure imgb0004
       in which
    • R 2 has the meaning given for 1 (above),
    • if appropriate in the presence of inert diluents.
    • Acrylic acid derivatives of the formula (II)
      Figure imgb0005
       in which
    • R, R 1 and R 3 have the meanings given at 2 (above).
  • 4. A process for the preparation of the new acrylic acid derivatives of the formula (II),
    Figure imgb0006
     in which
    • R , R and R 3 have the meanings given for 2 (above),
    • which is characterized in that 2-alkoxy-4-chloro-5-fluoro-benzoylacetic acid esters of the formula (IV)
      Figure imgb0007
       in weicner
    • R has the meaning given above and
    • R 4 represents alkyl, with orthoformic acid esters of the formula (V)
      Figure imgb0008
       in which
    • R 3 has the meaning given above, in the presence of acetic anhydride and, if appropriate, in the presence of diluents.
  • 5. 2-alkoxy-4-chloro-5-fluoro-benzoylacetic acid ester of the formula (IV)
    Figure imgb0009
     in which
    • R and R 4 have the meanings given at 4 (above).
  • 6. A process for the preparation of the new 2-alkoxy-4-chloro-5-fluoro-benzoylacetic acid esters of the formula (IV),
    Figure imgb0010
     in which
    • R and R 4 have the meanings given at 4 (above),
    • which is characterized in that acetophenones of the formula (VI)
      Figure imgb0011
       in which
    • R has the meaning given at 5 (above),
    • with carbonic acid dialkyl esters of the formula (VII)
      Figure imgb0012
       in which
    • R 4 has the meaning given for 5 (above), in the presence of strong bases
  • 7. Acetophenones of the formula (VI)
    Figure imgb0013
     in which
    • R has the meaning given at 5 (above).
  • 8. A process for the preparation of the acetophenones of the formula (VI),
    Figure imgb0014
     in which
    • R has the meaning given at 5 (above),
    • which is characterized in that 4-chloro-5-fluoro-2-hydroxacetophenone of the formula (VIII)
      Figure imgb0015
    • α) with allyl halides of the formula (IX)
      Figure imgb0016
       in which
    • R has the meaning given above and
    • Hal stands for halogen, or
    • β) with dialkyl sulfates of the formula (X)
      RO-SO 2 -OR (X) in which
    • R has the meaning given above, in the presence of acid acceptors and in the presence of diluents.
  • 9. 4-chloro-5-fluoro-2-hydroxyacetophenone of the formula (VIII)
    Figure imgb0017
  • 10. A process for the preparation of 4-chloro-5-fluoro-2-hydroxyacetophenone of the formula (VIII), characterized in that 3-chloro-4-fluorophenol of the formula (XI)
    Figure imgb0018
     with acetylating agents of the formula (XII)
    Figure imgb0019
     in which
    • W represents halogen or the radical CH 3 -COO-,

    in the presence of acylation catalysts and optionally in the presence of diluents.
  • 11. Use of compounds of formula (I) according to 1 (above), for the preparation of oxoquinoline carboxylic acid derivatives, characterized in that the compounds of formula (I) are cyclized and then converted to oxoquinoline carboxylic acid derivatives by known methods (cf., for example EP-OS 78 362).

Uberraschenderweise können mit Hilfe der erfindungsgemäßen Verbindungen der Formel (I) Oxochinolincarbonsäure-Derivate auf einfachere Weise und somit kostengünstiger hergestellt werden, als aus dem Stand der Technik bekannt ist (vgl. EP-OS 78 362). Nach dem Stand der Technik werden die substituierten Benzoylessigsäureethylester hergestellt,indem man z.B. Trihalogenmethylbenzol-Derivate verseift, die Säure mit Thionylchlorid in das entsprechende Benzoylchlorid überführt und danach mit Malonsäurediethylester in Gegenwart von Magnesiumalkoholat zum Benzoylmalonester-Derivat umsetzt. Anschließend wird durch partielle Verseifung und Decarboxylierung im wäßrigen Medium mit katalytischen Mengen p-Toluolsulfonsäure der Benzoylessigsäureethylester gebildet. Die weitere Umsetzung der Benzoylessigsäureethylester erfolgt zunächst analog zu dem in EP-OS 78 362 angegebenen Verfahren durch Umsetzung mit O-Ameisensäureester und anschließende Umsetzung mit Aminen. Danach erfolgt ein Ringschluß in Gegenwart von Säureakzeptoren und unter Abspaltung von Alkohol. Diese Verbindungen können anschließend nach bekannten Methoden zu den entsprechenden Oxochinolincarbonsäure-Derivaten weiterreagieren (vgl. z.B. EP-OS 78 362).Surprisingly, with the aid of the compounds of the formula (I) according to the invention, oxoquinoline carboxylic acid derivatives can be prepared in a simpler manner and therefore more cost-effectively than from the prior art is known (cf. EP-OS 78 362). According to the prior art, the substituted ethyl benzoylacetates are prepared by saponifying, for example, trihalomethylbenzene derivatives, converting the acid with thionyl chloride to the corresponding benzoyl chloride and then reacting it with diethyl malonate in the presence of magnesium alcoholate to give the benzoylmalonic ester derivative. Subsequently, the benzoylacetic acid ethyl ester is formed by partial saponification and decarboxylation in an aqueous medium with catalytic amounts of p-toluenesulfonic acid. The further reaction of the ethyl benzoylacetate is initially carried out analogously to the process specified in EP-OS 78 362 by reaction with O-formic acid ester and subsequent reaction with amines. This is followed by ring closure in the presence of acid acceptors and with the elimination of alcohol. These compounds can then react further by known methods to give the corresponding oxoquinoline carboxylic acid derivatives (cf., for example, EP-OS 78 362).

Die Erfindung betrifft vorzugsweise Verbindungen der Formel (I), in welcher

  • R für C1-C4-Alkyl steht,
  • R für C1-C4-Alkoxycarbonyl steht und
  • R 2 für C1-C4-Alkyl, C3-C6-Cycloalkyl, Amino C1-C4-Alkylamino oder Di-(C1-C4)-Alkylamino steht.
The invention preferably relates to compounds of the formula (I) in which
  • R represents C 1 -C 4 alkyl,
  • R represents C 1 -C 4 alkoxycarbonyl and
  • R 2 represents C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, amino C 1 -C 4 alkylamino or di- (C 1 -C 4 ) alkylamino.

Besonders bevorzugt sind die Verbindungen der Formel (I) in welcher

  • R für Methyl, Ethyl oder n-Propyl steht,
  • R für Methoxycarbonyl, Ethoxycarbonyl oder n-Propoxycarbonyl steht und
  • R 2 für Methyl, Ethyl, Cyclopropyl, Amino, (C1-C2)-Alkylamino oder Di-(C1-C2)-Alkylamino steht.
The compounds of the formula (I) in which are particularly preferred
  • R represents methyl, ethyl or n-propyl,
  • R represents methoxycarbonyl, ethoxycarbonyl or n-propoxycarbonyl and
  • R 2 represents methyl, ethyl, cyclopropyl, amino, (C 1 -C 2 ) alkylamino or di (C 1 -C 2 ) alkylamino.

Verwendet man beispielsweise für das erfindungsgemäße Verfahren (2) zur Herstellung der erfindungsgemäßen Verbindungen der Formel (I) 3-Ethoxy-2-(4-chlorfluor-2-ethoxy-benzoyl)-acrylsäureethylester und Cyclopropylamin als AUsgangsstoffe, so kann die Reaktion durch das folgende Formelschema wiedergegeben werden:

Figure imgb0020
If, for example, for the process (2) according to the invention for the preparation of the compounds of the formula (I) according to the invention, 3-ethoxy-2- (4-chlorofluoro-2-ethoxy-benzoyl) acrylic acid ester and cyclopropylamine are used as starting materials, the reaction can be carried out by the following formula scheme is shown:
Figure imgb0020

Die als Ausgangsstoffe für das erfindungsgemäße Verfahren (2) zu verwendenden Acrylsäure-Derivate sind durch die Formel (II) allgemein definiert. In dieser Formel stehen R und R bevorzugt für diejenigen Reste, welche oben für Formel (I) angegeben sind. R3 steht in dieser Formel für Alkoxy. Bevorzugt steht R 3 für C1-C4-Alkoxy.Formula (II) provides a general definition of the acrylic acid derivatives to be used as starting materials for process (2) according to the invention. In this formula, R and R preferably represent those radicals which are given above for formula (I). R 3 in this formula represents alkoxy. R 3 is preferably C 1 -C 4 alkoxy.

Die Verbindungen der Formel (II) sind neu. Sie lassen sich gemäß 4 (oben) herstellen (siehe weiter unten).The compounds of formula (II) are new. They can be manufactured according to 4 (above) (see below).

Als Beispiele für die Verbindungen der Formel (II) seien genannt:

Figure imgb0021
Figure imgb0022
Figure imgb0023
Figure imgb0024
Figure imgb0025
 The following may be mentioned as examples of the compounds of the formula (II):
Figure imgb0021
Figure imgb0022
Figure imgb0023
Figure imgb0024
Figure imgb0025

Die für das erfindungsgemäße Verfahren (2) außerdem als Ausgangsstoffe zu verwendenden Amine sind durch die Formel (III) allgemein definiert. In dieser Formel steht R 2 bevorzugt für diejenigen Reste, welche oben bei der Formel (I) angegeben sind.Formula (III) provides a general definition of the amines also to be used as starting materials for process (2) according to the invention. In this formula, R 2 preferably represents those radicals which are given above for formula (I).

Die Verbindungen der Formel (III) sind allgemein bekannte Verbindungen der organischen Chemie.The compounds of formula (III) are generally known compounds of organic chemistry.

Als Beispiele für die Verbindungen der Formel (III) seien genannt:

  • Methyl-, Ethyl-, n-Propyl-, i-Propyl-, n-Butyl-, i-Pentyl-, sec.-Butyl-, tert.-Butyl-, Cyclopropyl-, Cyclopentyl- und Cyclohexylamin; Hydrazin, Methylhydrazin, 1,1-Dimethylhydrazin, Ethylhydrazin und 1,1-Diethylhydrazin.
The following may be mentioned as examples of the compounds of the formula (III):
  • Methyl, ethyl, n-propyl, i-propyl, n-butyl, i-pentyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl and cyclohexylamine; Hydrazine, methylhydrazine, 1,1-dimethylhydrazine, ethylhydrazine and 1,1-diethylhydrazine.

Das erfindungsgemäBe Verfahren (2) zur Herstellung der neuen Verbindungen der Formel (I) wird bevorzugt unter Verwendung von Verdünnungsmitteln durchgeführt. Als Verdünnungsmittel kommen praktisch alle inerten organischen Lösungsmittel in Frage.Process (2) according to the invention for the preparation of the new compounds of the formula (I) is preferably carried out using diluents. Practically all inert organic solvents can be used as diluents.

Hierzu gehören insbesondere aliphatische und aromatische, gegebenenfalls halogenierte Kohlenwasserstoffe, wie Pentan, Hexan, Heptan, Cyclohexan, Petrolether, Benzin, Ligroin, Benzol, Toluol, Xylol, Methylenchlorid, Ethylenchlorid, Chloroform, Tetrachlorkohlenstoff, Chlorbenzol, o-Dichlorbenzol, Ether wie Diethyl- und Dibutylether, Glycoldimethylether und Diglycoldimethylether, Tetrahydrofuran und Dioxan und Alkohole wie Methanol, Ethanol, Isopropanol, Glykol.These include in particular aliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene, o-dichlorobenzene, ethers such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane and alcohols such as methanol, ethanol, isopropanol, glycol.

Das erfindungsgemäße Verfahren (2) wird im allgemeinen bei Temperaturen zwischen -20°C und +50°C durchgeführt. Bevorzugt wird der Bereich zwischen -10°C und 30°C. Die Umsetzungen werden im allgemeinen bei Normaldruck durchgeführt.Process (2) according to the invention is generally carried out at temperatures between -20 ° C. and + 50 ° C. The range between -10 ° C and 30 ° C is preferred. The reactions are generally carried out under normal pressure.

Zur Durchführung des erfindungsgemäßen Verfahrens (2) werden die Ausgangsstoffe gewöhnlich annähernd in äquimolaren Mengen eingesetzt. Ein Überschuß der einen oder anderen Reaktionskomponente bringt keine wesentlichen Vorteile. Die Aufarbeitung geschieht nach üblichen Methoden.To carry out process (2) according to the invention, the starting materials are usually used in approximately equimolar amounts. An excess of one or the other reaction component has no significant advantages. The processing takes place according to usual methods.

Verwendet man beispielsweise für das erfindungsgemäße Verfahren (4) zur Herstellung der erfindungsgemäßen Verbindungen der Formel (II) 4-Chlor-5-fluor-2-methoxy-benzoylessigsäuremethylester und Orthoameisensäuretriethylester als Ausgangsstoffe, so kann die Reaktion durch das folgende Formelschema wiedergegeben werden:

Figure imgb0026
If, for example, 4-chloro-5-fluoro-2-methoxy-benzoylacetic acid and triethyl orthoformate are used as starting materials for process (4) according to the invention for the preparation of the compounds of formula (II) according to the invention, the reaction can be represented by the following formula:
Figure imgb0026

Die als Ausgangsstoffe für das erfindungsgemäße Verfahren (4) zu verwendenden 2-Alkoxy-4-chlor-5-fluor- benzoylessigsäureester sind durch die Formel (IV) allgemin definiert. In dieser Formel steht R bevorzugt für diejenigen Reste, welche oben für Formel (I) angegeben sind.Formula (IV) provides a general definition of the 2-alkoxy-4-chloro-5-fluorobenzoylacetic acid esters to be used as starting materials for process (4) according to the invention. In this formula, R preferably represents those radicals which are given above for formula (I).

R4 steht in dieser Formel für Alkyl. Bevorzugt steht R 4 für C1-C4-Alkyl, besonders bevorzugt für Methyl, Ethyl, Isopropyl, Butyl.R 4 in this formula represents alkyl. R 4 is preferably C 1 -C 4 alkyl, particularly preferably methyl, ethyl, isopropyl or butyl.

Die Verbindungen der Formel (IV) sind neu. Sie lassen sich gemäß 6 (oben) herstellen (siehe weiter unten).The compounds of formula (IV) are new. They can be manufactured according to 6 (above) (see below).

Als Beispiele für die Verbindungen der Formel (IV) seien genannt:

Figure imgb0027
Figure imgb0028
 The following may be mentioned as examples of the compounds of the formula (IV):
Figure imgb0027
Figure imgb0028

Die für das erfindungsgemäße Verfahren (4) außerdem als Ausgangsstoffe zu verwendenden Orthoameisensäureester sind durch die Formel (V) allgemein definiert. R3 steht in dieser Formel für Alkoxy. Bevorzugt steht R3 für C'-C4-Alkoxy.Formula (V) provides a general definition of the orthoformic acid esters to be used as starting materials for process (4) according to the invention. R 3 in this formula represents alkoxy. R 3 is preferably C'-C4-alkoxy.

Die Verbindungen der Formel (V) sind allgemein bekannte Verbindungen der organischen Chemie.The compounds of formula (V) are generally known compounds of organic chemistry.

Als Beispiele für die Verbindungen der Formel (V) seien genannt:

  • Orthoameisensäure-methylester, -ethylester und -propylester.
The following may be mentioned as examples of the compounds of the formula (V):
  • Orthoformic acid methyl ester, ethyl ester and propyl ester.

Das erfindungsgemäße Verfahren (4) zur Herstellung der Verbindungen der Formel (II) wird bevorzugt ohne Verdünnungsmittel durchgeführt.Process (4) according to the invention for the preparation of the compounds of the formula (II) is preferably carried out without a diluent.

Das erfindungsgemäße Verfahren (4) wird im allgemeinen bei Temperaturen zwischen 80°C und 180°C durchgeführt. Bevorzugt wird der Bereich zwischen 100°C und 160°C. Die Umsetzungen werden im allgemeinen bei Normaldruck durchgeführt.Process (4) according to the invention is generally carried out at temperatures between 80 ° C. and 180 ° C. The range between 100 ° C. and 160 ° C. is preferred. The reactions are generally carried out under normal pressure.

Zur Durchführung des erfindungsgemäBen Verfahrens (4) zur Herstellung der Verbindungen der Formel (II) setzt man auf 1 Mol der Verbindung der Formel (IV), 1 bis 2 Mol, vorzugsweise 1,3 bis 1,7 Mol Orthoameisensäureester der Formel (V) und 2 bis 3 Mol, vorzugsweise 2 bis 2,5 Mol Acetanhydrid ein. Die Aufarbeitung des Reaktionsproduktes geschieht nach üblichen Methoden. Das Reaktionsprodukt kann auch ohne weitere Reinigung für die nächste Umsetzung eingesetzt werden.To carry out process (4) according to the invention for the preparation of the compounds of the formula (II), 1 mol of the compound of the formula (IV), 1 to 2 mol, preferably 1.3 to 1.7 mol, of orthoformic acid ester of the formula ( V ) are employed and 2 to 3 moles, preferably 2 to 2.5 moles, of acetic anhydride. The reaction product is worked up by customary methods. The reaction product can also be used for the next reaction without further purification.

Verwendet man beispielsweise für das erfindungsgemäße Verfahren (6) 2-Ethoxy-4-chlor-5-fluor-acetophenon und Kohlensäuredimethylester als Ausgangsstoffe, so kann die Reaktion durch das folgende Formelschema wiedergegeben werden:If, for example, 2-ethoxy-4-chloro-5-fluoro-acetophenone and dimethyl carbonic acid are used as starting materials for process (6) according to the invention, the reaction can be represented by the following formula:

Figure imgb0029
Figure imgb0029

Die als Ausgangsstoffe für das erfindungsgemäße Verfahren (6) zu verwendenden Acetophenone sind durch die Formel (VI) allgemein definiert. In dieser Formel steht R bevorzugt für diejenigen Reste, welche oben für Formel (I) angegeben sind.Formula (VI) provides a general definition of the acetophenones to be used as starting materials for process (6) according to the invention. In this formula, R preferably represents those radicals which are given above for formula (I).

Die Verbindungen der Formel (VI) sind neu. Sie lassen sich gemäß 8 (oben) herstellen (siehe weiter unten).The compounds of formula (VI) are new. They can be manufactured according to 8 (above) (see below).

Als Beispiele für die Verbindungen der Formel (VI) seien genannt:

  • 4-Chlor-5-fluor-2-methoxy-, 4-Chlor-5-fluor-2-ethoxy-, 4-Chlor-5-fluor-2-n-propoxy-, 4-Chlor-5-fluor-2-i-propoxy-, 4-Chlor-5-fluor-2-n-butoxy-, 4-Chlor-5-fluor-2-i-butoxy-, 4-Chlor-5-fluor-2-sec.-butoxy-und 4-Chlor-5-fluor-2-tert.-butoxy-acetophenon.
The following may be mentioned as examples of the compounds of the formula (VI):
  • 4-chloro-5-fluoro-2-methoxy-, 4-chloro-5-fluoro-2-ethoxy-, 4-chloro-5-fluoro-2-n-propoxy-, 4-chloro-5-fluoro-2 -i-propoxy, 4-chloro-5-fluoro-2-n-butoxy, 4-chloro-5-fluoro-2-i-butoxy, 4-chloro-5-fluoro-2-sec.-butoxy and 4-chloro-5-fluoro-2-tert-butoxy-acetophenone.

Die für das erfindungsgemäße Verfahren (6) außerdem als Ausgangsstoffe zu verwendenden Kohlensäuredialkylester sind durch die Formel (VII) allgemein definiert. In dieser Formel steht R4 für Alkyl. Bevorzugt steht R4für C1-C4-Alkyl.Formula (VII) provides a general definition of the dialkyl carbonates to be used as starting materials for process (6) according to the invention. In this formula, R 4 represents alkyl. R4 is preferably C 1 -C 4 alkyl.

Die Verbindungen der Formel (VII) sind bekannte Verbindungen der organischen Chemie.The compounds of formula (VII) are known compounds of organic chemistry.

Als Beispiele für die Verbindungen der Formel (VII) seien genannt:

  • Kohlensäuredimethylester, Kohlensäurediethylester und Kohlensäuredi-n-propylester.
The following may be mentioned as examples of the compounds of the formula (VII):
  • Carbonic acid dimethyl ester, carbonic acid diethyl ester and carbonic acid di-n-propyl ester.

Das erfindungsgemäße Verfahren (6) zur Herstellung der Verbindungen der-Formel (IV) wird vorzugsweise ohne Verdünnungsmittel durchgeführt. Bevorzugt wird in Gegenwart von überschüssigem Kohlensäuredialkylester der Formel (VII) gearbeitet.Process (6) according to the invention for the preparation of the compounds of the formula (IV) is preferably carried out without a diluent. It is preferred to work in the presence of excess dialkyl carbonate of the formula (VII).

Das erfindungsgemäße Verfahren (6) wird in Gegenwart von starken Basen durchgeführt. Besonders bewährt haben sich Alkalialkoholate, wie Natrium- und Kaliummethylat oder -ethylat und Kalium-tert.-butylat und Alkalihydroxide, wie Natrium- und Kaliumhydroxid.Process (6) according to the invention is carried out in the presence of strong bases. Alkaline alcoholates, such as sodium and potassium methylate or ethylate, and potassium tert-butoxide and alkali metal hydroxides, such as sodium and potassium hydroxide, have proven particularly useful.

Das erfindungsgemäße Verfahren (6) wird im allgemeinen bei Temperaturen zwischen 0°C und 140°C durchgeführt. Bevorzugt wird der Bereich zwischen 20°C und 120°C. Die Umsetzungen werden im allgemeinen bei Normaldruck durchgeführt.Process (6) according to the invention is generally carried out at temperatures between 0 ° C. and 140 ° C. The range between 20 ° C and 120 ° C is preferred. The reactions are generally carried out under normal pressure.

Das erfindungsgemäße Verfahren (6) setzt man auf 1 Mol der Verbindung der Formel (VI), 1 bis 3 Mol, vorzugsweise 1 bis 2,0 Mol einer starken Base und 5 bis 30 Mol, vorzugsweise 10 bis 25 Mol Kohlensäuredialkylester der Formel (VII) ein. Die Aufarbeitung erfolgt nach üblichen Methoden.Process (6) according to the invention is based on 1 mol of the compound of the formula (VI), 1 to 3 mol, preferably 1 to 2.0 mol of a strong base and 5 to 30 mol, preferably 10 to 25 mol of dialkyl carbonate of the formula (VII ) a. The processing takes place according to usual methods.

Verwendet man beispielsweise für das erfindungsgemäße Verfahren (8) 4-Chlor-5-fluor-2-hydroxyacetophenon der Formel (VIII) und Methyliodid bzw. Dimethylsulfat als Ausgangsstoffe, so kann die Reaktion durch das folgende Formelschema wiedergegeben werden:

Figure imgb0030
If, for example, 4-chloro-5-fluoro-2-hydroxyacetophenone of the formula (VIII) and methyl iodide or dimethyl sulfate are used as starting materials for process (8) according to the invention, the reaction can be represented by the following formula:
Figure imgb0030

Das als Ausgangsverbindung für das erfindungsgemäße Verfahren (8) zu verwendende 4-Chlor-5-fluor-2-hydroxy- acetophenon der Formel (VIII)..ist neu. Die Verbindung läßt sich gemäß 10 (oben) herstellen (genaue Beschreibung siehe weiter unten).The 4-chloro-5-fluoro-2-hydroxyacetophenone of formula (VIII) .. to be used as the starting compound for process (8) according to the invention is new. The connection can be established according to 10 (above) (for a detailed description see below).

Die für das erfindungsgemäße Verfahren (8) außerdem als Ausgangsstoffe zu verwendenden Alkylhalogenide bzw. Dialkylsulfate sind durch die Formel (IX) bzw. (X) allgemein definiert. In dieser Formel steht R bevorzugt für diejenigen Reste welche oben für Formel (I) angegeben sind.Formula (IX) and (X) generally define the alkyl halides or dialkyl sulfates to be used as starting materials for process (8) according to the invention. In this formula, R preferably represents those radicals which are given above for formula (I).

Die Verbindungen der Formeln (IX) und (X) sind allgemein bekannte Verbindungen der organischen Chemie. Als Beispiele für die Alkylhalogenide der Formel (IX) seien genannt:

  • Methylchlorid, Methylbromid, Methyliodid, Ethylbromid, Ethyliodid, n-Propylbromid, n-Propyliodid, i-Propylbromid, i-Propyliodid, n-Butylbromid, n-Butyliodid, i-Butylbromid, i-Butyliodid, sec.-Butylbromid, sec.-Butyliodid, tert."Butylbromid und tert.-Butyliodid.
The compounds of the formulas (IX) and (X) are generally known compounds of organic chemistry. The following may be mentioned as examples of the alkyl halides of the formula (IX):
  • Methyl chloride, methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, n-propyl bromide, n-propyl, i-propyl, i-propyl, n-butyl bromide, n-butyl iodide, i-butyl bromide, i -B utyliodid, sec-butyl bromide, sec. -Butyl iodide, tert. " Butyl bromide and tert-butyl iodide.

Als Beispiele für die Dialkylsulfate der Formel (X) seien genannt:

  • Dimethylsulfat, Diethylsulfat und Di-n-propylsulfat.
The following may be mentioned as examples of the dialkyl sulfates of the formula (X):
  • Dimethyl sulfate, diethyl sulfate and di-n-propyl sulfate.

Das erfindungsgemäße Verfahren (8) zur Herstellung der Verbindungen der (VI) wird vorzugsweise in Gegenwart von Wasser oder polaren organischen Solventien durchgeführt. Bevorzugt in Betracht kommen hierbei Ketone, wie z.B. Aceton, Methylethylketon, Methylisopropylketon und Methyl-isobutylketon, ferner Nitrile wie z.B. Acetonitril und Propionitril, außerdem Amide, wie Dimethylformamid, Dimethylacetamid und N-Methyl-pyrrolidon, sowie Ether, wie Diethyl- und Dibutylether, Glycoldimethylether und Diglycoldimethylether, Tetrahydrofuran und Dioxan.Process (8) according to the invention for the preparation of the compounds of (VI) is preferably carried out in the presence of water or polar organic solvents. Ketones, such as e.g. Acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, also nitriles such as e.g. Acetonitrile and propionitrile, also amides, such as dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone, and ethers, such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane.

Als Säureakzeptoren können bei der Durchführung des erfindungsgemäßen Verfahrens (8) vorzugsweise stark basische, jedoch schwach nucleophile Stoffe eingesetzt werden. Bevorzugt infrage kommen Natriumhydrid, Kaliumhydrid, Calciumhydrid, Natriumcarbonat, Kaliumcarbonat sowie Calciumcarbonat und Diazabicyclooctan (DABCO), Diazabicyclononen (DBN) und Diazabicycloundecen (DBU).When carrying out process (8) according to the invention, strongly basic but weakly nucleophilic substances can preferably be used as acid acceptors will. Sodium hydride, potassium hydride, calcium hydride, sodium carbonate, potassium carbonate and calcium carbonate and diazabicyclooctane (DABCO), diazabicyclonones (DBN) and diazabicycloundecene (DBU) are preferred.

Di Reaktionstemperatur kann beim erfindungsgemäßen Verfahren (8) zur Herstellung der neuen Verbindungen der Formel (II) innerhalb eines größeren Bereiches variiert werden. Im allgemeinen arbeitet man bei Temperaturen zwischen 0°C und +100°C, vorzugsweise zwischen 0°C und 80°C. Das erfindungsgemäße Verfahren (8) wird im allgemeinen unter Normaldruck durchgeführt.The reaction temperature in process (8) according to the invention for the preparation of the new compounds of the formula (II) can be varied within a substantial range. In general, temperatures between 0 ° C and + 100 ° C , preferably between 0 ° C and 80 ° C. Process (8) according to the invention is generally carried out under normal pressure.

Zur Durchführung des erfindungsgemäßen Verfahrens (8) setzt man auf 1 Mol der Verbindung der Formel (VIII), 1 bis 1,5 Mol, vorzugsweise 1 bis 1,2 Mol, Alkylierungsmittel der Formel (IX) bzw. (X) und 1 bis 1,5 Mol, vorzugsweise 1 bis 1,2 Mol, Säureakzeptor ein.To carry out process (8) according to the invention, 1 to 1.5 mol, preferably 1 to 1.2 mol, of alkylating agents of the formula (IX) or (X) and 1 to 1 mol of the compound of the formula (VIII) 1.5 moles, preferably 1 to 1.2 moles, of acid acceptor.

Die Umsetzungen werden im allgemeinen in einem geeigneten Verdünnungsmittel und gegebenenfalls in Gegenwart eines Säureakzeptors durchgeführt. Die Aufarbeitung geschieht nach üblichen Methoden.The reactions are generally carried out in a suitable diluent and, if appropriate, in the presence of an acid acceptor. The processing takes place according to usual methods.

Verwendet man beispielsweise für das erfindungsgemäße Verfahren (10) 3-Chlor-4-fluorphenol und Acetylchlorid als Ausgangsstoffe, so kann die Reaktion durch das folgende Formelschema wiedergegeben werden:

Figure imgb0031
Für das Verfahren (10) wird die Verbindung 3-Chlor-4- fluorphenol der Formel (XI) als Ausgangsverbindung verwendet.If, for example, 3-chloro-4-fluorophenol and acetyl chloride are used as starting materials for process (10) according to the invention, the reaction can be represented by the following formula:
Figure imgb0031
 For the process (10), the compound 3-chloro-4-fluorophenol of the formula (XI) is used as the starting compound.

3-Chlor-4-fluorphenol ist eine allgemein bekannte Verbindung der organischen Chemie.3-chloro-4-fluorophenol is a well known compound of organic chemistry.

Die für das Verfahren (10) außerdem als Ausgangsstoffe zu verwendenden Acetylierungsmittel sind durch die Formel (XII) allgemein definiert. In dieser Formel steht W für Halogen, wie insbesondere Fluor, Chlor oder Brom oder für den Rest CH3COO-.Formula (XII) provides a general definition of the acetylating agents which are also to be used as starting materials for process (10). In this formula, W represents halogen, such as, in particular, fluorine, chlorine or bromine or the remainder CH 3 COO-.

Die Verbindungen der Formel (XII) sind allgemein bekannte Verbindungen der organischen Chemie.The compounds of the formula (XII) are generally known compounds of organic chemistry.

Als Beispiele für die Verbindungen der Formel (XII) seien genannt:

  • Acetyl-fluorid, -chlorid und -bromid und Essigsäureanhydrid.
The following may be mentioned as examples of the compounds of the formula (XII):
  • Acetyl fluoride, chloride and bromide and acetic anhydride.

Die Acylierung wird in Gegenwart bekannter Acylierungskatalysatoren durchgeführt. Als Acylierungskatalysatoren kommen für das Verfahren (10) bevorzugt Friedel-Crafts-Katalysatoren infrage. Hierzu gehören Aluminiumhalogenide, wie Aluminiumtrichlorid sowie Bortrifluorid.The acylation is carried out in the presence of known acylation catalysts. Friedel-Crafts catalysts are preferred acylation catalysts for process (10). These include aluminum halides such as aluminum trichloride and boron trifluoride.

Das erfindungsgemäße Verfahren (10) wird bevorzugt ohne Verdünnungsmittel durchgeführt.Process (10) according to the invention is preferably carried out without a diluent.

Das erfindungsgemäbe Verfahren (10) wird im allgemeinen bei Temperaturen zwischen 0°C und 120°C durchgeführt. Bevorzugt wird der Bereich zwischen 20°C und 100°C. Die Umsetzungen werden im allgemeinen bei Normaldruck durchgeführt.Process (10) according to the invention is generally carried out at temperatures between 0 ° C. and 120 ° C. The range between 20 ° C and 100 ° C is preferred. The reactions are generally carried out under normal pressure.

Zur Durchführung des erfindungsgemäßen Verfahrens (10) setzt man auf 1 Mol 3-Chlor-4-fluorphenol der Formel (XI), 1 bis 2,2 Mol, vorzugsweise 1 bis 1,8 Mol, Acetylierungsmittel der Formel (XII) und 1 bis 3,5 Mol, vorzugsweise 1 bis 2,8 Mol, Acylierungskatalysator ein.To carry out process (10) according to the invention, 1 mol of 3-chloro-4-fluorophenol of the formula (XI), 1 to 2.2 mol, preferably 1 to 1.8 mol, of acetylating agent of the formula (XII) and 1 to 3.5 moles, preferably 1 to 2.8 moles, of an acylation catalyst.

Die Aufarbeitung erfolgt in üblicher Weise z.B. durch Zugabe von Eis oder Eiswasser zum Rekaitonsgemisch nach beendeter Reaktion und durch Absaugen des erkaltenen Produkts.The processing takes place in the usual way e.g. by adding ice or ice water to the Rekaiton mixture after the reaction has ended and by suctioning off the cooled product.

Die Verbindungen der Formel (I) können als Zwischenprodukte für die Synthese von Oxochinolincarbonsäure-Derivaten verwendet werden, die eine hervorragende bakterizide Wirksamkeit besitzen (vgl. z.B. EP-OS 78 362). Diese lassen sich daraus gemäß folgendem Formelschema herstellen:

Figure imgb0032
Y = H, AlkylThe compounds of formula (I) can be used as intermediates for the synthesis of oxoquinoline carboxylic acid derivatives which have excellent bactericidal activity (cf., for example, EP-OS 78 362). These can be produced from it according to the following formula scheme:
Figure imgb0032
 Y = H, alkyl

Die Cyclisierung der Verbindungen der Formel (I) zu der bekannten Verbindungen der Formel (XIII) wird in Gegenwart von Verdünnungsmitteln und in Gegenwart von Säureakzeptoren bei Temperaturen zwischen 60°C bis 300°C vorzugsweise bei 80°C bis 180°C, durchgeführt.The cyclization of the compounds of formula (I) to the known compounds of formula (XIII) is carried out in the presence of diluents and in the presence of acid acceptors at temperatures between 60 ° C to 300 ° C, preferably at 80 ° C to 180 ° C.

Als Verdünnungsmittel können Dioxan, Dimethylsulfoxid, N-Methyl-pyrrolidon, Sulfolan, Hexamethylphosphorsäuretriamid und bevorzugt N,N-Dimethylformamid verwendet werden.Dioxane, dimethyl sulfoxide, N-methyl-pyrrolidone, sulfolane, hexamethylphosphoric acid triamide and preferably N, N-dimethylformamide can be used as diluents.

Als Säureakzeptoren kommen für diese Umsetzung Kalium- tert.-butanolat, Butyl-lithium, Lithium-phenyl, Phenylmagnesiumbromid, Natriummethylat, Natriumhydrid und besonders bevorzugt Kalium- oder Natriumcarbonat in Betracht.Potassium tert-butoxide, butyl lithium, lithium phenyl, phenyl magnesium bromide, sodium methylate, sodium hydride and particularly preferably potassium or sodium carbonate are suitable acid acceptors for this reaction.

Bei der Durchführung der Cyclisierung setzt man auf 1 Mol der Verbindung der Formel (I) 1 bis 1,6 Mol, vorzugsweise 1 bis 1,3 Mol Säureakzeptor ein.When carrying out the cyclization, 1 to 1.6 mol, preferably 1 to 1.3 mol, of acid acceptor are used per 1 mol of the compound of the formula (I).

Die Aufarbeitung des Reaktionsproduktes erfolgt in üblicher Weise. Die weiteren Umsetzungen der Verbindungen der Formel (XIII) zu den bekannten Verbindungen der Formeln (XIV) und (XV) sind bereits beschrieben worden (vgl. z.B. EP-OS 78 362 und EP-OS 113 092).The reaction product is worked up in a conventional manner. The further reactions of the compounds of the formula (XIII) to the known compounds of the formulas (XIV) and (XV) have already been described (see e.g. EP-OS 78 362 and EP-OS 113 092).

HerstellungsbeispieleManufacturing examples Beispiel 1example 1

Figure imgb0033
Figure imgb0033

Eine Lösung von 10,3 g (0,034 Mol) 2-(4-Chlor-5-fluor-2-methoxy-benzoyl)-3-methoxy-acrylsäuremethylester in 40 ml Ethanol wird unter Eiskühlung und Rühren tropfenweise mit 2 g (0,034 Mol) Cyclopropylamin versetzt und 2 Stunden bei 20°C weitergerührt. Der Niederschlag wird kalt abgesaugt und mit wenig Ethanol nachgewaschen.A solution of 10.3 g (0.034 mol) of 2- (4-chloro-5-fluoro-2-methoxy-benzoyl) -3-methoxy-acrylic acid methyl ester in 40 ml of ethanol is added dropwise with 2 g (0.034 mol ) Cyclopropylamine added and stirring continued at 20 ° C for 2 hours. The precipitate is suctioned off cold and washed with a little ethanol.

Man erhält 5,5 g (48,6 % der Theorie) 2-(4-Chlor-5-fluor-2-methoxy-benzoyl)-3-cyclopropylamino-acrylsäuremethylester vom Schmelzpunkt 128°C - 132°C.5.5 g (48.6% of theory) of 2- (4-chloro-5-fluoro-2-methoxy-benzoyl) -3-cyclopropylamino-acrylic acid methyl ester of melting point 128 ° C.-132 ° C. are obtained.

Herstellung der Verbindungen der Formel (II)Preparation of the compounds of formula (II) Beispiel (11-1)Example (11-1)

Figure imgb0034
Figure imgb0034

Ein Gemisch aus 9,6 g (0,037 Mol) 4-Chlor-5-fluor-2-methoxy-benzoylessigsäuremethylester, 5,5 g (0,054 Mol) Orthoameisensäuretrimethylester und 8,7 g (0,087 Mol) Essigsäureanhydrid wird 3 Stunden unter Rückfluß erhitzt. Anschließend werden bei Normaldruck im Wasserstrahlvakuum und zuletzt im Hochvakuum bei einer Badtemperatur von 120°C bis 130°C die flüchtigen Bestandteile abdestilliert.A mixture of 9.6 g (0.037 mol) of 4-chloro-5-fluoro-2-methoxy-benzoylacetic acid methyl ester, 5.5 g (0.054 mol) of trimethyl orthoformate and 8.7 g (0.087 mol) of acetic anhydride is heated under reflux for 3 hours . The volatile constituents are then distilled off at atmospheric pressure in a water jet vacuum and finally in a high vacuum at a bath temperature of 120 ° C. to 130 ° C.

Man erhält 10,3 g rohrer 2-(4-Chlor-5-fluor-2-methoxybenzoyl)-3-methoxy-acrylsäuremethylester. Das Produkt kann ohne weitere Aufarbeitung in die nächste Reaktionsstufe eingesetzt werden.10.3 g of tubular 2- (4-chloro-5-fluoro-2-methoxybenzoyl) -3-methoxy-acrylic acid methyl ester are obtained. The product can be used in the next reaction step without further work-up.

Herstellung der Verbindungen der Formel (IV)Preparation of the compounds of the formula (IV) Beispiel (IV-1)Example (IV-1)

Figure imgb0035
Figure imgb0035

Aus einer Mischung von 210 ml Kohlensäurediemthylester une 8,9 g (0,165 Mol) Natriummethylat destilliert man 30 ml Kohlensäuredimethylester ab und tropft dann unter Sieden innerhalb von 3 Stunden eine Lösung von 30,4 g (0,15 Mol) 4-Chlor-5-fluor-2-methoxy-acetophenon in 75 ml Kohlensäuredimethylester zum Reaktionsgemisch. Das bei der Reaktion entstehende Methanol wird dabei über eine Kolonne abdestilliert. Nach der Zugabe wird noch 3 Stunden unter Rückfluß gekocht, dann destilliert man das Lösungsmittel im Vakuum ab. Den Rückstand löst man in 500 ml Wasser, gibt bei 10°C konzentrierte Salzsäure zu, bis ein pH von 6 erreicht ist und extrahiert dann zweimal mit je 200 ml Methylenchlorid. Die organische Phase wird über Natriumsulfat getrocknet, im Vakuum eingedampft und dann im Hochvakuum bei 120°C andestilliert. Auf diese Weise erhält man 2,4 g des eingesetzten 4-Chlor-5-fluor-2-methoxy-acetophenons zurück.30 ml of dimethyl carbonate are distilled off from a mixture of 210 ml of dimethyl carbonate and 8.9 g (0.165 mol) of sodium methylate, and a solution of 30.4 g (0.15 mol) of 4-chloro-5 is then added dropwise over 3 hours while boiling -fluoro-2-methoxy-acetophenone in 75 ml of dimethyl carbonate to the reaction mixture. The methanol formed in the reaction is distilled off over a column. After the addition boiled under reflux for a further 3 hours, then the solvent is distilled off in vacuo. The residue is dissolved in 500 ml of water, concentrated hydrochloric acid is added at 10 ° C. until a pH of 6 is reached and the mixture is then extracted twice with 200 ml of methylene chloride. The organic phase is dried over sodium sulfate, evaporated in vacuo and then distilled in a high vacuum at 120 ° C. In this way, 2.4 g of the 4-chloro-5-fluoro-2-methoxy-acetophenone used are obtained.

Als Rückstand bleiben 32 g (89 % der Theorie) 4-Chlor-5-fluor-2-methoxy-benzoylessigsäuremethylester in Form eines hellbraunen Pulvers mit dem Schmelzpunkt 61°C zurück.32 g (89% of theory) of 4-chloro-5-fluoro-2-methoxy-benzoylacetic acid methyl ester remain in the form of a light brown powder with a melting point of 61 ° C. as a residue.

Herstellung der Verbindungen der Formel (VI)Preparation of the compounds of the formula (VI) Beispiel (VI-1)Example (VI-1)

Figure imgb0036
Figure imgb0036

Ein Gemisch aus 7,5 g (0,04 Mol) 4-Chlor-5-fluor-2-hydroxy-acetophenon, 8,3 g (0,06 Mol) Kaliumcarbonat, 50 ml Acetonitril und 6,3 g (0,044 Mol) Methyliodid wird 7 Stunden bei 55°C gerührt. Anschließend wird das Reaktionsgemisch filtriert und das Filtrat im Vakuum eingedampft. Der Rückstand wird mit 50 ml Wasser verrieben und abgesaugt.A mixture of 7.5 g (0.04 mol) of 4-chloro-5-fluoro-2-hydroxy-acetophenone, 8.3 g (0.06 mol) of potassium carbonate, 50 ml of acetonitrile and 6.3 g (0.044 mol ) Methyl iodide is stirred at 55 ° C for 7 hours. The reaction mixture is then filtered and the filtrate evaporated in vacuo. The residue is triturated with 50 ml of water and suction filtered.

Man erhält so 7,4 g (92 % der Theorie) 4-Chlor-5-fluor-2-methoxy-acetophenon in Form eines beigen Pulvers mit dem Schmelzpunkt 80°C.7.4 g (92% of theory) of 4-chloro-5-fluoro-2-methoxy-acetophenone are thus obtained in the form of a beige powder with a melting point of 80 ° C.

Herstellung der Verbindung der Formel (VIII)Preparation of the compound of formula (VIII)

Figure imgb0037
Figure imgb0037

Zu einer Mischung aus 11,8 g (0,08 Mol) 3-Chlor-4-fluor- phenol und 26,8 g (0,2 Mol) Aluminiumchlorid tropft man bei 20 bis 30°C 9,5 g (0,12 Mol) Acetylchlorid. Das Gemisch wird 1 Stunde bei 95 bis 100°C gerührt und dann noch heiß auf ein Gemisch aus 300 g Eis und 100 ml Wasser gegeben. Nach 30 Minuten saugt man das ausgefallene Produkt ab und wäscht gut mit Wasser nach.To a mixture of 11.8 g (0.08 mol) of 3-chloro-4-fluorophenol and 26.8 g (0.2 mol) of aluminum chloride, 9.5 g (0, 12 moles) acetyl chloride. The mixture is stirred for 1 hour at 95 to 100 ° C and then added hot to a mixture of 300 g of ice and 100 ml of water. After 30 minutes, the precipitated product is suctioned off and washed well with water.

Man erhält so 12,9 g (86 % der Theorie) 4-Chlor-5-fluor-2-hydroxy-acetophenon in Form eines.beigen Pulvers mit dem Schmelzpunkt 72°C.This gives 12.9 g (86% of theory) of 4-chloro-5-fluoro-2-hydroxy-acetophenone in the form of a beige powder with a melting point of 72 ° C.

Herstellung der Verbindungen der Formel (XIII)Preparation of the compounds of the formula (XIII)

Figure imgb0038
Figure imgb0038

Eine Suspension von 5,2 g (0,016 Mol) 2-(4-Chlor-5-fluor-2-methoxy-benzoyl)-3-cyclopropylamino-acrylsäuremethylester (Beispiel 1), 2,6 g (0,019 Mol) Kaliumcarbonat und 25 ml Dimethylformamid wird 2 Stunden auf ca. 150°C erhitzt. Anschließend wird das Reaktionsgemisch auf Eis gegossen, der Niederschlag abgesaugt und mit Wasser nachgewaschen. Nach dem Trocknen im Vakuumtrockenschrank bei 100°C werden 3,6 g Rohprodukt erhalten.A suspension of 5.2 g (0.016 mol) of 2- (4-chloro-5-fluoro-2-methoxy-benzoyl) -3-cyclopropylamino-acrylic acid methyl ester (Example 1), 2.6 g (0.019 mol) of potassium carbonate and 25 ml of dimethylformamide is heated to approx. 150 ° C for 2 hours. The reaction mixture is then poured onto ice, the precipitate is filtered off with suction and washed with water. After drying in a vacuum drying cabinet at 100 ° C., 3.6 g of crude product are obtained.

Nach Umkristallisation aus Ethanol erhält man 3,1 g (66 % der Theorie) 7-Chlor-1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-chinolincarbonsäuremethylester vom Schmelzpunkt 244°C - 245°C.After recrystallization from ethanol, 3.1 g (66% of theory) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid methyl ester of melting point 244 ° C. - 245 ° C. are obtained.

Claims (11)

1. Aminoacrylsäure-Derivate der Formel (I)
Figure imgb0039
in welcher R für Alkyl steht, R1 für Alkoxycarbonyl steht und R 2 für Alkyl, Cycloalkyl, Amino, Alkylamino oder Di-alkylamino steht. 1. Aminoacrylic acid derivatives of the formula (I)
Figure imgb0039
 in which R represents alkyl, R 1 represents alkoxycarbonyl and R 2 represents alkyl, cycloalkyl, amino, alkylamino or di-alkylamino. 2. Verfahren zur Herstellung der neuen Aminoacrylsäure-Derivate der Formel (I)
Figure imgb0040
in welcher R für Alkyl steht, R1 für Alkoxycarbonyl steht und R 2 für Alkyl, Cycloalkyl, Amino, Alkylamino oder Di-alkylamino steht, dadurch gekennzeichnet, daß man Acrylsäure-Derivate der Formel (II) in welcher
Figure imgb0041
 R und R die oben angegebenen Bedeutungen haben und R 3 für Alkoxy steht mit Aminen der Formel (III)
Figure imgb0042
in welcher R 2 die oben angegebene Bedeutung hat, gegebenenfalls in Gegenwart von inerten Verdünnungsmitteln umsetzt. 2. Process for the preparation of the new aminoacrylic acid derivatives of the formula (I)
Figure imgb0040
 in which R represents alkyl, R 1 represents alkoxycarbonyl and R 2 is alkyl, cycloalkyl, A mino, alkylamino or di-alkylamino, characterized in that acrylic acid derivatives of the formula (II) in which
Figure imgb0041
 R and R have the meanings given above and R 3 is A lkoxy with amines of the formula (III)
Figure imgb0042
 in which R 2 has the meaning given above, if appropriate in the presence of inert diluents. 3. Acrylsäure-Derivate der Formel (II)
Figure imgb0043
in welcher R für Alkyl steht, R1 für Alkoxycarbonyl steht, R3 für Alkoxy steht. 3. Acrylic acid derivatives of the formula (II)
Figure imgb0043
 in which R represents alkyl, R 1 represents alkoxycarbonyl, R 3 represents alkoxy. 1. Verfahren zur Herstellung der Acrylsäure-Derivate der Formel (II),
Figure imgb0044
in welcher R für Alkyl steht, R1 für Alkoxycarbonyl steht, R 3 für Alkoxy steht, dadurch gekennzeichnet daß man 2-Alkoxy-4-chlor-5-fluor-benzoylessigsäureester der Formel (IV)
Figure imgb0045
in welcher R die oben angegebene Bedeutung hat und R 4 für Alkyl steht, mit Orthoameisensäureestern der Formel (V)
Figure imgb0046
in welcher R 3 die oben angegebene Bedeutung hat, in Gegenwart von Acetanhydrid und gegebennfalls in Gegenwart von Verdünnungsmitteln umsetzt. 1. Process for the preparation of the acrylic acid derivatives of the formula (II),
Figure imgb0044
 in which R represents alkyl, R 1 represents alkoxycarbonyl, R 3 represents alkoxy, characterized in that 2-alkoxy-4-chloro-5-fluoro-benzoylacetic acid esters of the formula (IV)
Figure imgb0045
 in which R has the meaning given above and R 4 represents alkyl, with orthoformic acid esters of the formula (V)
Figure imgb0046
 in which R 3 has the meaning given above, in the presence of acetic anhydride and optionally in the presence of diluents. 5. 2-Alkoxy-4-chlor-5-fluor-benzoylessigsäureester der Formel (IV) in welcher
Figure imgb0047
 R für Alkyl steht und R 4 für Alkyl steht. 5. 2-alkoxy-4-chloro-5-fluoro-benzoylacetic acid ester of the formula (IV) in which
Figure imgb0047
 R represents alkyl and R 4 represents alkyl. 6. Verfahren zur Herstellung der neuen 2-Alkoxy-4-chlor-5-fluor-benzoylessigsäureester der Formel (IV), in welcher
Figure imgb0048
R für Alkyl steht und R 4 für Alkyl steht, dadurch gekennzeichnet, daß man Acetophenone der Formel (VI)
Figure imgb0049
in welcher R die oben angegebene Bedeutung hat, mit Kohlensäuredialkylestern der Formel (VII)
Figure imgb0050
in welcher R4 die (oben) angegebene Bedeutung hat, in Gegenwart von starken Basen umsetzt. 6. Process for the preparation of the new 2-alkoxy-4-chloro-5-fluoro-benzoylacetic acid esters of the formula (IV), in which
Figure imgb0048
 R represents alkyl and R 4 represents alkyl, characterized in that acetophenones of the formula (VI)
Figure imgb0049
 in which R has the meaning given above, with carbonic acid dialkyl esters of the formula (VII)
Figure imgb0050
 in which R 4 has the meaning given above, in the presence of strong bases. 7. Acetophenone der Formel (VI)
Figure imgb0051
in welcher R für Alkyl steht. 7. Acetophenones of the formula (VI)
Figure imgb0051
 in which R represents alkyl. 8. Verfahren zur Herstellung der Acetophenone der Formel (VI)
Figure imgb0052
in welcher R für Alkyl steht, dadurch gekennzeichnet, daß man 4-Chlor-5-fluor-2-hydroxyacetophenon der Formel (VIII)
Figure imgb0053
 α) mit Alkylhalogeniden der Formel (IX)
Figure imgb0054
in welcher R die oben angegebene Bedeutung hat und Hal für Halogen steht, oder B) mit Dialkylsulfaten der Formel (X)
Figure imgb0055
in welcher R die oben angegebene Bedeutung hat, in Gegenwart von Säureakzeptoren und in Gegenwart von Verdünnungsmitteln umsetzt. 8. Process for the preparation of the acetophenones of the formula (VI)
Figure imgb0052
 in which R represents alkyl, characterized in that 4-chloro-5-fluoro-2-hydroxyacetophenone of the formula (VIII)
Figure imgb0053
 α) with alkyl halides of the formula (IX)
Figure imgb0054
 in which R has the meaning given above and Hal represents halogen, or B) with dialkyl sulfates of the formula (X)
Figure imgb0055
 in which R has the meaning given above, in the presence of acid acceptors and in the presence of diluents. 9. 4-Chlor-5-fluor-2-hydroxyacetophenon der Formel (VIII)
Figure imgb0056
 9. 4-chloro-5-fluoro-2-hydroxyacetophenone of the formula (VIII)
Figure imgb0056
 10. Verfahren zur Herstellung von 4-Chlor-5-fluor-2-hydroxyacetophenon der Formel (VIII), dadurch gekennzeichnet, daß man 3-Chlor-4-fluorphenol der Formel (XI)
Figure imgb0057
mit Acetylierungsmitteln der Formel (XII)
Figure imgb0058
in welcher W für Halogen oder den Rest CH3-COO- steht, in Gegenwart von Acylierungskatalysatoren und gegebenenfalls in Gegenwart von Verdünnungsmitteln umsetzt. 10. A process for the preparation of 4-chloro-5-fluoro-2-hydroxyacetophenone of the formula (VIII), characterized in that 3-chloro-4-fluorophenol of the formula (XI)
Figure imgb0057
 with acetylating agents of the formula (XII)
Figure imgb0058
 in which W represents halogen or the radical CH3-COO-, in the presence of acylation catalysts and optionally in the presence of diluents. 11. Verwendung von Verbindungen der Formel (I) gemäß 1 (oben), zur Herstellung von Oxochinolincarbonsäure-Derivaten, dadurch gekennzeichnet, daß man die Verbindungen der Formel (I) cyclisiert und anschließend nach bekannten Methoden zu Oxochinolincarbonsäure-Derivaten umsetzt.11. Use of compounds of formula (I) according to 1 (above), for the preparation of oxoquinoline carboxylic acid derivatives, characterized in that the compounds of formula (I) are cyclized and then converted to oxoquinoline carboxylic acid derivatives by known methods.
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